Age-related hearing loss is a consequence of accumulated environmental stresses to the cochlea and an intrinsic genetically-controlled aging process, with as much as 60% of hearing losses in the elderly being attributable to heritability. The often uncertain medical and noise histories in human subjects coupled with the high variability in the age of onset, rate of progression and the nature and severity of the hearing impairments make it difficult to attribute presbyacusis to a specific cause. Moreover, this phenotypic variability and other characteristics strongly suggest that age-related hearing loss is a complex polygenic disorder possibly involving different alleles on multiple genes. Recent advances in next generation sequencing have provided a powerful new tool to address the genetic basis of many age-related diseases. Here we propose to investigate the genetic and molecular basis of human presbyacusis. This project takes advantage of our extensive and continuously growing database containing well documented medical, noise and auditory function histories along with DNA samples from large numbers of human subjects. It also capitalizes on the development of new algorithms based on audiograms and data from animal models to define specific age-related hearing loss phenotypes in our experimental subjects. Accordingly, we propose to perform a comprehensive population-based cohort molecular genetic study to provide information about genetic contributions to specific phenotypes and biological pathways involved with age-related hearing loss. Aim 3.1 recruits additional subjects to increase the size of our discovery and replication cohorts. Aim 3.2 identifies genetic variants associated with increased susceptibility to presbyacusis employing genome-wide association analysis using whole exome sequence data. Aim 3.3 determines the pathological and potential functional consequences of genetic variants causing age-related hearing loss by assessing the distribution and changes in the expression pattern of promising candidate gene products and their association with pathological changes in human temporal bones.